Receptor tyrosine kinases (RTKs) are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain.
The human epidermal-growth-factor receptor (HER) family consists of four distinct polypeptides, each with a cytoplasmic sequence homologous to other protein tyrosine kinases. Surveys have shown that HER1 and HER2 are over expressed in many tumor types. HER1 has been shown to be over expressed in the majority of solid tumors, and can be activated by either autocrine expression of ligand(s) or paracrine ligand expression by stromal elements. HER1 expression has been demonstrated in as much as 80-90% of colon and non-small cell lung cancer (NSCLC). HER2 gene amplification and over expression of the protein have been shown to occur in about 30% of all breast cancer. Clinical studies have shown unequivocally that HER2 gene amplification is a prognostic indicator for poor outcome in breast cancer. In addition to breast cancer, there is a good correlation between HER2 gene amplification and over expression in gastric, salivary gland, and bladder cancer. Co-expression of HER1 and HER2 has been demonstrated in breast, ovarian, bladder, and gastric tumors, as well as squamous cell carcinoma of the head and neck (SCCHN). Since HER1 and HER2 form heterodimers that are activated by EGF and related ligands, heterodimer signaling is believed to play a significant role in the pathobiology of these tumors as well as in their resistance to agents targeting only one of the receptors. Receptor coexpression in tumor cells suggests that targeting both HER1 and HER2 will be more effective in modulating proliferation than inhibiting either receptor alone. Herceptin®, which targets HER2 overexpressing cells, has no effect on HER2/HER1 heterodimerization.
Vascular endothelial growth factor (VEGF) is a mitogenic growth factor that is required for tumor angiogenesis and signals through the VEGF receptor 2 (VEGFR2) on endothelial cells. Inhibition of VEGF signaling has been shown to be a clinically proven approach for treating solid tumors, most notably colon and NSCLC. The epidemiology of HER1 and HER2 expression in tumors (both homo-and heterodimers), together with the expression of VEGFR2 in the vasculature that support tumor growth, suggest that a molecule that targets these three signal transduction pathways in both tumor and endothelial cells will result in greater efficacy than inhibiting individual pathways alone.
(3R,4R)-4-amino-1-[[4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol is a potent inhibitor of HER1, HER2, HER4, and VEGFR2, which has demonstrated broad antiproliferative activity in various tumor cell lines and excellent anti-tumor efficacy in HER2 and HER1 driven tumor xenograft models.
(3R,4R)-4-amino-1-[[4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol, has the structure of formula I:
and is referred to herein as “Compound I”. Compound I inhibits the tyrosine kinase activity of growth factor receptors such as HER1, HER2, and HER4 thereby making it useful as an anti-cancer agent. Compound I is disclosed in US 20050182058A1, published Aug. 18, 2005, which is assigned to the present assignee and is incorporated herein by reference in its entirety.
Typically, in the preparation of a pharmaceutical composition, a form of the active ingredient is sought that has a balance of desired properties such as dissolution rate, solubility, bioavailability, and/or storage stability. For example, it is desired that a form of the active ingredient, which has the requisite solubility and bioavailability, also has sufficient stability that it does not convert during manufacture or storage of the pharmaceutical composition to a different form, which has different solubility and/or bioavailability. One or more forms of Compound I are desired having properties and stability that allow the preparation of pharmaceutical compositions suitable for the treatment of diseases such as cancer. Further, one or more forms of Compound I are desired that allow the isolation and/or purification of Compound I, for example, during a preparative process.
It has been found through extensive testing of the various forms isolated that Form N-2 is more thermodynamically stable than Form N-1 at temperatures from room temperature to 50° C. Form N-1 melts at about 137° C. and recrystallizes as Form N-2, which then melts at about 150° C. Additionally, slurried mixtures of N-1 and N-2 convert to Form N-2 indicating it is monotropically more stable.